YTB323 (Rapcabtagene Autoleucel) Demonstrates Durable Efficacy and a Manageable Safety Profile in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Phase I Study Update

Background: CD19-directed CAR-T cell therapies (tx) have shown efficacy in patients (pts) with B-cell malignancies. However, many pts fail to respond or experience disease relapse after initial response. YTB323 (rapcabtagene autoleucel) is an autologous CD19-directed CAR-T cell tx generated by the innovative T-Charge™ platform, which produces CAR-T cells by a rapid manufacturing process (2 days) preserving T-cell stemness. This methodology is expected to increase CAR-T cell persistence and expansion and yield higher efficacy and a manageable safety profile. Here we present efficacy and safety, dose exposure, and biomarker analyses for rapcabtagene autoleucel in adults with r/r DLBCL in the ongoing Phase I, multicenter, dose-escalation study (NCT03960840).

Methods: Eligible pts had r/r DLBCL after ≥2 lines of prior tx, measurable disease at enrollment, and ECOG 0-1. Pts received single-dose rapcabtagene autoleucel at targeted dose level (DL) 1 (2.5×10⁶ CAR+ cells), DL2 (12.5×10⁶ CAR+ cells), DL3 (25×10⁶ CAR+ cells), or DL4 (40×10⁶ CAR+ cells). Primary endpoints characterized safety and dose-limiting toxicities to identify a recommended dose. Secondary endpoints include response rate by local investigator assessment and cellular kinetics.

Results: As of March 31, 2022, 45 pts with r/r DLBCL received rapcabtagene autoleucel: 4 at DL1, 28 at DL2, 7 at DL3, and 6 at DL4. Median age was 64.8 y, 67% received 2 prior lines of tx, and 29% had prior autologous stem cell transplant. Median (range) time since most recent relapse/progression was 2.8 (1.4-81.8) mo. Pts were followed for a median (range) of 10 (0.3-29) mo. Complete response (CR) rate at DL2 was 65%. CR at DL2, excluding pts in CR before rapcabtagene autoleucel (due to either a late effect of prior tx or bridging chemotherapy), was 61%. Responses at DL2 were durable, with CR rates of 63% (12/19) at 3 mo and 69% (11/16) at 6 mo (Figure 1). Median duration of response at DL2 was not reached. Of 45 pts evaluable for safety, 96% reported 1 adverse event (AE) of any grade (Gr) and 89% had ≥1 AE Gr ≥3. Cytokine release syndrome (CRS) was experienced by 15 pts (33%): 1 at DL1, 10 at DL2, 2 at DL3, and 2 at DL4. One DL2 pt (4%) experienced Gr 4 CRS. CRS was managed with tocilizumab, corticosteroids, and vasopressors in 7 (70%), 3 (30%), and 1 (10%) pts at DL2, respectively, and 1 DL3 pt (50%) received tocilizumab. Median (range) time to CRS onset was 9 (1-36) d and resolution was 5 (1-18) d. Five pts (11%) had immune effector cell-associated neurotoxicity syndrome (ICANS) events: 3 at DL2 and 2 DL4. Two DL2 pts (7%) experienced Gr 3 ICANS (no pts experienced Gr 4-5). Median (range) time to onset and resolution of ICANS was 16 (6-28) and 16 (1-36) d, respectively. ICANS management was based on dexamethasone, methylprednisolone, and anakinra in 2 (67%), 1 (33%), and 1 (33%) pts at DL2, respectively, and 1 DL4 pt (50%) received dexamethasone. Median time to peak rapcabtagene autoleucel expansion was delayed compared with tisagenlecleucel: 16 d at DL2 vs 9 d in JULIET. At a 25-fold lower dose, rapcabtagene autoleucel expansion at DL2 was comparable by qPCR to tisagenlecleucel expansion in JULIET. Expansion increased from DL1 to DL2 with no further increases at higher doses. Data from DL2 show CAR transgene was detectable by qPCR in 1 out of 2 pts with 12 mo follow-up. scRNAseq analysis shows the rapcabtagene autoleucel manufacturing process preserves T-cell fitness by retaining the composition of cell populations from apheresis to final product through the short manufacturing time. scRNAseq analysis also suggests that certain characteristics of the final product composition may lead to improved CR rates at 3 mo. B-cell aplasia (≤50 CD19+ cells/μL) was established before/after rapcabtagene autoleucel in all pts. In responders, B-cell aplasia persisted for ≥8 mo.

Conclusions: Rapcabtagene autoleucel is a potent new CD19-directed CAR-T cell tx with distinct cellular kinetics, durable efficacy, and a manageable safety profile. DL2 (12.5×10⁶) CAR+ viable T cells is the recommended dose for Phase III studies, based on the CR rate, favorable safety profile, and cellular kinetics. Updated results with expanded cellular kinetics and biomarker analyses will be presented at the meeting.

Barba:Amgen: Honoraria; Pfizer: Honoraria; Gilead: Honoraria; Novartis: Honoraria; BMS: Honoraria. Kwon:Novartis: Consultancy, Honoraria, Other: Support for attending meetings and/or travel; BMS: Consultancy; Gilead: Consultancy, Honoraria, Other: Support for attending meetings and/or travel. Briones:BMS: Consultancy, Honoraria; Gilead: Consultancy; Novartis: Consultancy, Honoraria; GSK: Consultancy; Takeda: Consultancy, Honoraria; Celgene/BMS: Research Funding; HOSPITAL SANTA CREU I SANT PAU: Current Employment. Jaeger:Roche: Consultancy, Honoraria, Research Funding; Miltenyi Biomedicine: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Research Funding; Gilead: Honoraria; BMS Celgene: Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Honoraria; Sanofi: Honoraria; MSD: Honoraria; Beigene: Honoraria; Incyte: Honoraria; Acerta: Honoraria. Bachy:Amgen, BMS: Research Funding; Kite, Gilead, Novartis, Roche, Incyte, Miltenyi Biotech, Takeda, Sanofi: Honoraria; Roche, Gilead, ADC Therapeutics, Takeda, Novartis, Incyte: Membership on an entity's Board of Directors or advisory committees; Hospices Civils de Lyon: Current Employment. Boissel:GILEAD: Honoraria; AMGEN: Honoraria; ARIAD/INCYTE: Honoraria; ASTELLAS: Honoraria; NOVARTIS: Honoraria; SERVIER: Honoraria. Kato:Novartis: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Other: Grants or contracts from any entity ; Chugai: Consultancy, Honoraria, Other: Grants or contracts from any entity ; Meiji: Consultancy, Honoraria; Kyowa-Kirin: Honoraria, Other: Grants or contracts from any entity ; Takeda: Honoraria, Other: Grants or contracts from any entity ; AbbVie: Other: Grants or contracts from any entity ; Eisai: Other: Grants or contracts from any entity ; Janssen: Other: Grants or contracts from any entity ; Celgene: Other: Grants or contracts from any entity ; Ono: Other: Grants or contracts from any entity . Shah:Bristol Myers Squibb: Consultancy; Lilly Oncology: Consultancy, Honoraria; Incyte Corporation: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy; Epizyme: Consultancy; Kite Pharma: Consultancy; Miltenyi Biotec: Consultancy, Research Funding; TG therapeutics: Consultancy. Frigault:Kite/Gilead: Consultancy, Research Funding; Arcellx: Research Funding; Cytoagents: Consultancy; JnJ/Legend: Consultancy; Iovance: Consultancy; Novartis: Consultancy, Research Funding; BMS: Consultancy. Riedell:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Nektar Therapeutics: Membership on an entity's Board of Directors or advisory committees; Intellia Therapeutics: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sana Biotechnology: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Research Funding; Calibr: Research Funding; Tessa Therapeutics: Research Funding; Fate Therapeutics: Research Funding; Xencor: Research Funding. Teshima:Luca Science Inc.: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Manuscript preparation, Research Funding; Janssen: Other: Manuscript preparation; NIPPON SHINYAKU: Research Funding; Fuji Pharma: Research Funding; TEIJIN PHARMA: Research Funding; Astellas: Research Funding; Chugai: Research Funding; Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck Sharp & Dohme: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding; Kyowa Kirin: Honoraria, Research Funding. Ciceri:Kite Pharma: Consultancy. Pearson:Novartis: Current Employment. Orlando:Novartis: Current Employment. Davis:Novartis: Current Employment, Current equity holder in private company. Masood:Novartis: Current Employment, Current holder of stock options in a privately-held company. Flinn:Vincerx Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Acerta Pharma: Research Funding; AstraZeneca: Consultancy, Research Funding; Forma Therapeutics: Research Funding; Incyte: Research Funding; IGM Biosciences: Research Funding; Forty Seven: Research Funding; Agios: Research Funding; ArQule: Research Funding; Trillium Therapeutics: Research Funding; Century Therapeutics: Consultancy; Genentech: Consultancy, Research Funding; Genmab: Consultancy; Hutchison MediPharma: Consultancy; Gilead Sciences: Research Funding; Unum Therapeutics: Research Funding; Rhizen Pharmaceuticals: Research Funding; Celgene: Research Funding; Constellation Pharmaceuticals: Research Funding; Curis: Research Funding; Pharmacyclics: Consultancy, Research Funding; Merck: Research Funding; Iksuda Therapeutics: Consultancy; Infinity Pharmaceuticals: Research Funding; Loxo@Lilly: Research Funding; Abbvie: Consultancy, Research Funding; Pfizer: Research Funding; Portola Pharmaceuticals: Research Funding; Novartis: Consultancy, Research Funding; Seattle Genetics: Research Funding; MorphoSys: Consultancy, Research Funding; Takeda: Consultancy; Servier Pharmaceuticals: Consultancy; Kite Pharma: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; InnoCare Pharma: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Fate Therapeutics: Research Funding; Epizyme: Research Funding; CTI Biopharma: Research Funding; Millenium Pharmaceuticals: Research Funding; CALIBR: Research Funding; CALGB: Research Funding; Bristol Myers Squibb: Research Funding; Secura Bio: Consultancy; Xencor: Consultancy; Biopath: Research Funding; Myeloid Therapeutics: Research Funding; Roche: Consultancy, Research Funding; Nurix Therapeutics: Consultancy, Research Funding; City of Hope National Medical Center: Research Funding; TCR2 Therapeutics: Research Funding; Tessa Therapeutics: Research Funding; Triphase Research & Development Corp: Research Funding; 2seventy bio: Research Funding. Dickinson:Roche, BMS, Novartis, Kite, Gilead, NKARTA, AdiCet Bio, Interius, Janssen, MSD, Amgen: Honoraria; Roche, BMS, Novartis, Kite, Gilead, NKARTA, AdiCet Bio, Interius, Janssen, MSD: Consultancy; Roche, Novartis, Kite, Gilead, MSD, Takeda, Celgene: Research Funding.